Myocardial protection in cardiac surgery—hindsight from the 2020s

Summary

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Myocardial protection and specifically cardioplegia have been extensively investigated in the beginnings of cardiac surgery. After cardiopulmonary bypass had become routine, more and more cardiac operations were possible, requiring reliable and reproducible protection for times of blood flow interruptions to the most energy-demanding organ of the body. The concepts of hypothermia and cardioplegia evolved as tools to extend cardiac ischaemia tolerance to a degree considered safe for the required operation. A plethora of different solutions and delivery techniques were developed achieving remarkable outcomes with cross-clamp times of up to 120 min and more. With the beginning of the new millennium, interest in myocardial protection research declined and, as a consequence, conventional cardiac surgery is currently performed using myocardial protection strategies that have not changed in decades. However, the context, in which cardiac surgery is currently performed, has changed during this time. Patients are now older and suffer from more comorbidities and, thus, other organs move more and more into the centre of risk assessment. Yet, systemic effects of cardioplegic solutions have never been in the focus of attention. They say hindsight is always 20–20. We therefore review the biochemical principles of ischaemia, reperfusion and cardioplegic extension of ischaemia tolerance and address the concepts of myocardial protection with ‘hindsight from the 2020s’. In light of rising patient risk profiles, minimizing surgical trauma and improving perioperative morbidity management becomes key today. For cardioplegia, this means accounting not only for cardiac, but also for systemic effects of cardioplegic solutions.

METABOLIC BACKGROUND TO MYOCARDIAL PROTECTION

The heart is the largest producer and consumer of energy per gram of tissue in the body [1] and it produces energy in form of adenosine triphosphate (ATP) and other high-energy phosphates mainly by oxidizing fatty acids and carbohydrates. It generates per day 35 times its own weight in ATP, of which it only possesses 300 mg [2]. Thus, the continuous supply of oxygen to the heart is essential for maintaining contractile function. The interruption of regional or global blood flow to the heart is generally referred to as ischaemia and consists of an interruption of both oxygen and substrate supply [3]. With the onset of ischaemia, contractile function first decreases and then quickly seizes. Resumption of coronary flow after an episode of ischaemia is referred to as reperfusion [4]. If reperfusion sets in before irreversible damage has occurred, contractile function of the heart can partially or fully be restored. Although reperfusion is a ‘conditio sine qua non’ for potential recovery from ischaemia, reperfusion itself may induce additional detrimental mechanisms that may cause myocardial injury, also known as reperfusion injury [5]. In practice, it is difficult to distinguish ischaemic from reperfusion injury, but the existence of reperfusion injury has been proven by the fact that postischaemic modulations are able to reduce damage from an ischaemic episode [6]. Because of these close connections of ischaemia and reperfusion and because of the difficulties in distinguishing the origin of ischaemia and reperfusion associated alterations, the term ischaemia/reperfusion injury has been coined and the 2 terms are often used in conjunction.

The timeframe that is tolerable for an ischaemic heart before irreversible injury sets in is generally considered the ischaemia tolerance of the heart [7]. The actual time of ischaemia tolerance depends on the metabolic activity of the heart. Smaller hearts with higher resting heart rates (e.g. rats or mice) show shorter time periods of ischaemia tolerance than larger hearts with higher resting heart rates (e.g. pigs, dogs). In the human heart, irreversible damage from ischaemia is thought to set in after ∼20 min under normothermic conditions [8]. From a practical standpoint, this timeframe is rather short to perform complex surgical procedures such as coronary artery bypass grafting, valve replacements or repair, let alone combined procedures. Thus, after the ability to reproducibly establish cardiopulmonary bypass (CPB), the need for longer times to exclude the heart from the circulation grew [9]. Figure 1A schematically illustrates the principle of ischaemia tolerance and the intended extension of this time frame through protective strategies.

The first practically applied metabolic principle to extend the myocardium’s ischaemia tolerance was the application of hypothermia. Figure 1B shows the original measurements of Bigelow and colleagues who subjected dogs to whole body hypothermia and assessed myocardial oxygen consumption [10]. This reduction in oxygen consumption through cooling would extend the timeframe for a cardiac procedure on the ischaemically arrested heart still allowing subsequent recovery of function. Surgeons at that time operated under the motto ‘operate as fast and as cold as possible’ [11]. While whole body hypothermia not only extended the ischaemia tolerance of the heart but also that of other organs, this principle is still applied today, specifically when the brain requires protection during operations with total circulatory arrest [12].

In parallel to the investigations of the impact of hypothermia on slowing myocardial metabolism, other approaches assessed the effect of deliberately arresting the contractile apparatus (mainly by modifying the cells’ membrane potentials) on ischaemia tolerance, suggesting that reducing energy demand would also slow myocardial energy consumption and the need for ATP production. This concept was named cardioplegia and several different principles of arresting the heart were explored (see below). Figure 1C shows the impact of ventricular fibrillation or cardioplegic arrest on oxygen consumption during CPB compared to the beating state in a pig model [13]. The figure nicely illustrates that arresting contractile activity through cardioplegic solutions substantially reduces oxygen consumption, which is supplementary to the effect of slowing myocardial metabolism through hypothermia. It is therefore no surprise that cold cardioplegia (blood or crystalloid) is currently the most frequently applied technique to extend myocardial ischaemia during cardiac surgery worldwide [14].

These developments have had a remarkable impact on the care of patients with cardiovascular disease requiring a surgical procedure and a plethora of different cardioplegic solutions and different techniques for their application have been developed and are still being used today. The central figure shows a summarizing scheme of the protective but also of potentially detrimental effects of cardioplegia and the dynamic interplay of these factors with outcome. The following text explains its rationale starting with a brief review of the different cardioplegic solutions and their clinical outcomes.

COMPARISON OF DIFFERENT CARDIOPLEGIC SOLUTIONS AND THEIR DELIVERY TECHNIQUES

The different cardioplegic solutions can be characterized by solvent (crystalloid versus blood), composition and mechanism of arrest (extra- versus intracellular, hyper- versus depolarizing), temperature (cold versus warm), delivery route (antegrade versus retrograde) and repetition necessity (single shot versus intermittent versus continuous). They all affect the cell’s action potential eliminating the spontaneous generation and the propagation of electrical impulses that usually elicit myocardial contraction. Figure 2 schematically illustrates how the action potential interacts with the ECG and ion fluxes across the cellular membrane. Cardioplegic solutions with low Na⁺ concentrations (e.g. Bretschneider-HTK solution) eliminate the fast sodium influx and arrest the action potential in a hyperpolarized state. Solutions with high potassium concentrations inhibit the potassium efflux during repolarization and arrest the action potential in a depolarized state (e.g. Calafiore [15], etc.). Combinations are also possible. Del Nido solution for instance inhibits both potassium efflux by high concentration of K+, thereby achieving rapid depolarized arrest, and sodium influx with Lidocaine acting as sodium channel blocker polarizing the membrane to some degree. In every case, electrical excitation of the contractile apparatus is blocked, and no propagation of electrical signals is possible anymore (impressively visible if an implanted pacemaker is present). In addition, modulation of Ca²⁺ and Mg²⁺ concentrations directly interferes with excitation-contraction coupling by blocking the mechanisms that induce actin-myosin interaction leading to contraction. The result is a still and soft heart that can easily be manipulated for the required surgical procedure.

Knowing the molecular mechanisms, the question of how long the heart can safely be arrested arises. We performed a systematic review of the literature to assess the relationship of cardioplegia on mortality. Table 1 shows a summary of the main clinical evidence. Despite the immense variability in application protocols and conditions, the outcomes are surprisingly close to each other. For instance, Øvrum et al. performed 2 RCTs comparing blood versus crystalloid cardioplegia in patients undergoing coronary artery bypass grafting (CABG) [16] or aortic valve replacement [17]. None of the perioperative characteristics such as the need and dose of inotropes, ventilation duration and spontaneous sinus rhythm after cross-clamping showed any differences between the groups and even in high-risk patients, perioperative outcomes were similar. In a meta-analysis by Guru et al. [18], an association of using blood cardiolegia and less cardiac low output syndrome and lower cardiac enzyme levels was observed, while there were similar rates of myocardial infarctions and death. In contrast, another meta-analysis by Sá et al. [19] revealed similar rates of death, myocardial infarction and cardiac low output between the same 2 types of cardioplegic strategies.

The Warm Heart Trial randomized CABG patients to receiving either warm or cold blood cardioplegia and, similar to the findings described above, no significant impact of cardioplegia temperature on survival and perioperative morbidity was observed [20]. A meta-analysis by Fan et al. addressed the same question. Despite the fact that lower cardiac enzyme levels were observed after warm blood cardioplegia as well as higher postoperative cardiac indices, this did not translate into significant differences in mortality and morbidity [21].

Another way myocardial damage can manifest itself is swelling of cardiomyocytes. The complexity in assessing oedema due to cardioplegia lies in the fact that oedema itself is an inevitable consequence of ischaemic/reperfusion injury. Nevertheless, a study by Mehlhorn et al. [22] found no differences of blood cardioplegia in preventing myocardial oedema compared to crystalloid cardioplegia in an animal model.

Others looked for differences in peri- and postoperative outcomes addressing the delivery route and need for repetition of the individual cardioplegic solution. In a small RCT on patients undergoing valve replacement with either antegrade or retrograde cold blood cardioplegia, Dagenais et al. [23] could not identify one of the approaches to be superior in terms of perioperative survival, stroke, infarction rates and cardiac enzyme release. Another RCT [24] of comparable size on CABG patients found higher postoperative troponin levels after antegrade cardioplegia delivery. Similar to Guru et al. [18], the authors interpreted increased cardiac enzyme levels as a reflection of inferior myocardial protection. This suggestion appears plausible as cardiac biomarker release has been used as an indicator of myocardial injury for decades. Nevertheless, the true value of such release especially in the setting of cardiac surgery remains a matter of debate [25, 26]. It is well conceivable that at least some of the biomarker amount released in the setting of cardiac surgery does not reflect irreversible damage to the myocardium [25] and this amount may be different depending on the cardiopegic solution or delivery route used.

Last but not least, comparing single shot versus multi-dose administration of cardioplegia was subject to a meta-analysis by Gambardella et al. [27] and, again, no difference in mortality and myocardial infarction rate was observed.

MISSION ACCOMPLISHED?

Summarizing the findings from our systematic search, one may conclude that today’s cardioplegic principles and myocardial protection strategies are of equal value. It is, thus, no surprise that a ‘mission accomplished’ attitude has developed [28], which has been supported by continuous improvements in mortality and morbidity after cardiac surgery over the last decades [29].

Reflecting on these issues from the 2020s, a more critical conclusion may be drawn. All current myocardial protection strategies have remained unchanged for decades. The youngest solutions (i.e. del Nido’s and Calafiore) have been introduced in the 1990s almost 30 years ago reflecting a certain trough in clinical and academic interest in this field. Table 2 compares the number of publications on myocardial protection related to all publications in cardiac surgery between the 1990s and 2010s. The total number has been cut in half and the relative percentage has decreased by a factor of 5. This decline in interest may be understandable from all the above-described results. However, since myocardial protection solutions and strategies have not changed in these decades, the advancements in clinical outcomes during this time [29] cannot be attributed to improvements in myocardial protection.

Thus, looking back at myocardial protection from today, the mission cannot be seen as accomplished because several issues have not been or were insufficiently addressed. Most importantly, patient profiles have changed but myocardial protection has not. Today, patients are much different from those in the early days of myocardial protection research as they are older and carry more comorbidities. These conditions had always been excluded from randomized trials and have never been specifically addressed experimentally. Moreover, the impact of other cofactors such as ischaemia duration, baseline cardiac function and extra-cardiac effects of cardioplegia have never been investigated in detail, either. Yet, the literature provides some clues suggesting that addressing these points may reveal new potential for innovation in myocardial protection.

CARDIO-SPECIFIC EFFECTS OF CARDIOPLEGIA (X-CLAMP TIME, AGE AND RIGHT VENTRICULAR FUNCTION)

A cardioprotective strategy extends myocardial ischaemia tolerance but one has to recognize that even the time frame of ‘protected’ blood flow interruption may not be harmless. We had addressed this issue before by analysing mortality in relation to cross-clamp times in about 30 000 patients who had undergone adult cardiac surgery at the Toronto General Hospital [30]. There was a close relationship between mortality and extending aortic cross-clamp times, which was even most visible in patients with normal ejection fraction. Similar findings were reported by Banner et al. [31] in ∼1500 patients after heart transplant where longer cardioplegic ischaemia times during transplantation were related to a higher 30-day mortality.

Plotting the relationship between aortic cross-clamp time and 30-day mortality using the data from our systematic literature search further confirms this association (Fig. 3A). However, the figure reveals another important recognition. There appears to be a striking difference in the ability of cardioplegia to extend ischaemia tolerance between younger and older patients. Age is one of the most relevant co-factors traditionally increasing postoperative morbidity and mortality. It is per se associated with a higher incidence of comorbidities and advanced cardiac disease, but it has also been identified as additional, independent risk factor in most analyses [32]. Other commonly accepted clinical confounders, besides patient age, were tested during the meta-regression analysis and did not exhibit a similarly significant impact on the risk ratio of perioperative mortality and aortic cross-clamp time. Thus, other factors in addition to the classic comorbidities we monitor preoperatively must contribute to perioperative risk. One of those might be decreased myocardial ischaemia tolerance with increasing age.

Limited ischaemia tolerance with older age has been demonstrated in animal models [33] and also in in vitro analyses on human right atrial myocardium [34]. In the human studies, illustrated in Fig. 3B and C, muscle samples were subjected to simulated hypoxia or ischaemia and reperfusion. Functional recovery was significantly reduced in myocardium from older patients compared to samples from younger individuals. Moreover, –this association also applies to younger hearts which exhibit higher tolerance to ischaemia. An example of this can be found in the accumulated experience of myocardial protection in congenital cardiac surgery among paediatric and neonate patients, as described in the recent review by Bradić et al. [35]. The specific impact of age on the relationship of cross-clamp times and outcomes has never been specifically assessed in the context of cardioplegia but affects a growing fraction of patients undergoing at times complex and therefore lengthy operations.

One confounding factor in the context of cardioplegia and cardioplegic arrest is the unconditional necessity for CPB, which may add additional trauma to the heart. It is interesting to note that avoiding the use of CPB in on-pump vs off-pump bypass surgery may actually deliver improved outcomes in high-risk patients [36]. In patients undergoing invasive treatment of aortic stenosis, data from the PARTNER 3 trial (randomization of patients with severe aortic stenosis and low surgical risk to either surgical, SAVR or transfemoral aortic valve implantation [37]) proposed right ventricular dysfunction in the majority of patients after SAVR, but not after transfemoral aortic valve implantation. The authors found reduced tricuspid annulus plane systolic excursion in the SAVR group which persisted up to 1 year of follow-up. Similar observations were made by others [38, 39] who also found reduced tricuspid annulus plane systolic excursion after CPB. However, right ventricular ejection fraction and stroke volume remained unchanged [39, 40]. Further investigations are missing and the previous suggestions are unlikely to be clinically relevant because long-term outcomes currently tilt in the direction of classic surgery [41–43]. In any case, it is conceivable that the right ventricle in these (often older) patients might specifically be susceptible to ischaemic damage during cardioplegic arrest. Thus, the areas of age and right ventricular dysfunction in the context of cardioplegic arrest and myocardial ischaemia tolerance currently wait to be investigated in detail.

EXTRA-CARDIAC EFFECTS OF CARDIOPLEGIA (VASOPLEGIA, RENAL DYSFUNCTION, CEREBRAL DYSFUNCTION)

During the application of cardioplegia, various amounts of the applied fluid will find access to the systemic circulation and extra-cardiac effects of cardioplegia have been described with the potential to negatively affect outcome.

VASOPLEGIA

Low systemic vascular resistance (SVR) is a well-known phenomenon observed in patients undergoing cardiac surgery with CPB. It is characterized by hypotension with normal or elevated cardiac output and usually normal or decreased filling pressures despite adequate volume substitution. Low SVR is associated with higher morbidity rates and prolonged recovery with longer intensive care unit (ICU) and in-hospital stay [44]. Low SVR as shown by Carrel et al. [44] is associated with the total volume of infused cardioplegic solution. Moreover, it seems that specific cardioplegic solutions (e.g. HTK, del Nido solutions) lead to more severe vasoplegia and require higher vasopressor/inotropic support in the perioperative period than others [45, 46]. Thus, the pharmacologic mechanisms of cardiac arrest applied by different solutions (e.g. membrane hyperpolarization versus depolarisation, Fig. 2) may affect not only cardiomyocytes but also vascular smooth muscle cells [47] (Fig. 4A). Interestingly, this vasoplegic effect can significantly be reduced by scavenging the cardioplegic solution from the coronary sinus during its application avoiding its entry into the systemic circulation [46] (Fig. 4B).

RENAL DYSFUNCTION

Perioperative renal dysfunction is a dreaded complication associated with increased morbidity and mortality [48]. The impact of cardioplegia on its development is not really clear, yet. Cheungpasitporn et al. [49] demonstrate less acute renal failure after off-pump compared to on-pump surgery, allowing a potential link of acute renal failure also to cardioplegia. Sanetra et al. [50] demonstrated less acute renal failure by using del Nido cardioplegia compared to cold blood cardioplegia. However, this comparison suffers from the high risk of type I error as an acute kidney injury was investigated as one of the many other (20) secondary outcomes. The authors conclude that a randomized trial with renal parameters as primary outcomes should be conducted. Indeed, the direct impact of cardio-protective solutions on renal function has only been assessed in animals [51]. Some solutions (e.g. HTK) were extensively investigated in isolated kidney models [52]. However, in these studies, it was the goal to preserve the kidneys for organ transplantation and not to assess the impact of cardioprotective strategies on renal function.

While the greatest risk factor for perioperative acute kidney injury is pre-existing renal insufficiency [53], postoperative renal function may also be affected by factors such as perioperative hypotension, need for inotropic support [54] (e.g. in cases of low SVR or vasoplegia—see above) or low perioperative haematocrit [55]. It is therefore well conceivable that distinct cardioplegic strategies lead to different levels of hemodilution [56] and vasoplegia [46], which may potentially contribute to additional renal injury.

CEREBRAL DYSFUNCTION

Cardiac surgery may be complicated by cerebral dysfunction, which is most often related to ischaemic and/or embolic complications [57]. Cardioplegia has been associated with cerebral dysfunction based on changes in the electrolyte status (e.g. systemic hyponatremia [58] or the induction of hemodilution [59]). Some studies demonstrated higher incidences of stroke in warm [60] and retrograde [61] cardioplegia and suggested a link to microembolizations [62] from the more frequent repetitive administration compared to single shot techniques. Others found postoperative delirium [58], seizures [63] (in paediatric patients), as well as cerebral inflammation [64] (which has been observed in animal models) connected to the use of cardioplegia. However, the explanations of these observations often lack consistent plausibility and systematic investigations of cardioplegia effects on cerebral function have not been performed.

CURRENT INNOVATIONS

Despite the described decline in research interest in the field, some innovations were made in the recent past but never really saw the light of the operating room. Dobson and colleagues [65] applied a hyperpolarizing normokalemic solution incorporating adenosine and lidocaine as the cardioprotective and arresting agents in a rat model and described superior protection compared to St Thomas’ Hospital solution. The authors attributed these benefits to reduced reperfusion injury by the mitigation of 5 key negative factors associated with depolarizing hyperkalemic cardioplegia, namely: (i) membrane and cellular ionic imbalance, (ii) coronary vasoconstriction, (iii) coronary endothelial damage, (iv) postoperative rhythm and conduction disturbances and (v) stunning of cardiomyocytes and the syndrome of low cardiac output. Yet, this academically developed strategy has found only limited clinical application [66]. A similar positive effect of cardiomechanical arrest with a polarized membrane of cardiomyocytes has been described by other authors when hyperpolarizing solutions, yet to gain widespread clinical use, are applied [67, 68]. An innovation that just entered the clinical arena is Custodiol-N, an industry-sponsored successor to the classic Bretschneider solution. In animal studies, it showed superior cardiac and endothelial function [69] and a prospective randomized clinical trial in CABG patients [70] showed a reduction in biomarker (CK-MB) release compared to classic Bretschneider solution. Custodiol-N is now available for daily practice, 30 years after its youngest competitor took this step.

Another avenue in optimizing myocardial protection against ischaemic/reperfusion injury involves the techniques of pre- and post-conditioning. Several studies have shown apparent positive results in animal models [71] or in the intervention treatment of myocardial infarction [72]. However, a randomized study by Hausenloy et al. [73] did not demonstrate similar effects for daily cardiac surgery.

CONCLUSION AND FUTURE PERSPECTIVE

Current strategies of myocardial protection allow the conduct of modern cardiac surgery achieving results that have not been surpassed in long-term treatment effect by any alternative, yet. This recognition is remarkable, specifically considering that myocardial protection strategies have not changed in 3–5 decades. However, it is also sobering in light of the gaps in evidence that we have described above. This article is therefore a call to action for scientifically inclined cardiac surgeons and researchers interested in myocardial protection and ischaemia/reperfusion. Some of the areas in need have been outlined here and include the role of age, other organ (e.g. kidney, liver, brain) functions as well as (right) ventricular function. There appears to be ample room for improvement if patients enter the operating room awake and compensated (which should be the case in every elective operation) and require inotropes and intensive medical care after a symptom-causing and life-limiting cardiac problem has been surgically solved. The logic says there must be a better way. It is up to us to find it.

FUNDING

No funding is received for this review.

Conflict of interest: none declared.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.

Author contributions

Murat Mukharyamov: Formal analysis; Investigation; Visualization; Writing—original draft. Ulrich Schneider: Conceptualization; Methodology; Validation. Hristo Kirov: Conceptualization; Methodology. Tulio Caldonazo: Conceptualization; Methodology. Torsten Doenst: Project administration; Supervision; Validation; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Oyvind Jakobsen, Paul Kurlansky and the other, anonymous reviewers for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CPB

  Cardiopulmonary bypass

 
• SVR

  Systemic vascular resistance

Author notes